Lysosomal storage disease

Lysosomal storage disease:
A group of more than 40 genetic disorders that result when a specific organelle in our body s cells – the lysosome – malfunctions.

The lysosome processes unwanted material into substances that the cell can utilize.

Lysosomes break down this unwanted matter via enzymes, highly specialized proteins essential for survival.
Tay-Sachs
(GM2 Gangliosidosis)
Etiology of Tay-Sachs dis.
It is due to deficiency in hexoseaminidase A ? subunit.
Ch. By accumulation of gangliosides, principly in the brain, as aresult of a deficiency of a catabolic lysosomal enzyme.
The main affected site is the brain.
Microscopical changes: foamy cells.
EM finding whorled configuration within lysosomes.
Molecular bases of Tay-Sachs disease:
Misfolded of mutant protein “unfolded protein” response.
If this protein are not stabilized by chaperones (a protein that assists the non-covalent folding/unfolding ) , they trigger apoptosis.
Dx. 1. By estimation of hexosaminidase enz. level .
2. By DNA analysis.
Cl/F:
Normal at birth motor weakness begin at 3-6 M foll by mental retardation, blindness and severe neurologic dysfunction.
Death within 2-3 y.
Niemann-Pick Disease, Type A&B
Due to deficiency of acid sphingomyelinase.
Accumulation of sphingomyelin.
Type A severe deficiency of sphingomyelinase.
Impair breakdown of sphingomyelin into ceramide and phosphorylcholine.
Dx Enz assay, DNA probe.
The most severly affected org. are:
(Liver, spleen, BM,and lung +entire CNS).
Cl/F of NP A&B:
Present in infancy with:
Severe neurological deterioration.
Visceromegaly (Hepatosplenomegaly).
Dx:
Estimation of sphingmyelinase in leukocyte or cultured fibroblast.
Antenatal dx by enz. Assay or DNA probe analysis.
NP C:
Due to mutation in NPC1 or NPC2 genes.
Primarly due to defect in lipid transport.
Accumulation of cholesterol & GM1 &GM2 gangliosides
More common than NPA&NPB.
The most common type present in childhood with ataxia, vertical supranuclear gaze palsy, dystonia, dysarthria & psychomotor regression.
Gausher Disease:

Mutation in the gene that encodes glucosylceramidase that lead to deficiency of this enzyme.
Accumulating of toxic metabolites “glucocerebroside”.
Mucopolysaccharidosis
Disease due to :
Deficiency of one of the 11 enzymes required to break down these sugar chains into simpler molecules.
Production of enzymes that do not work properly.
Over time, these glycosaminoglycans collect in the cells, blood and connective tissues.
The result is permanent, progressive cellular damage which affects appearance, physical abilities, organ and system functioning, and, in most cases, mental development.